The primary goal of this research program is to discover new natural products that will lead to novel anti-cancer drugs. Overall, we expect to generate a large number of exciting new natural products for development as novel anti-cancer agents using the powerful tools of microbial genomics, combinatorial biology, combinatorial biosynthesis, natural products chemistry and innovative anti-cancer drug screening assay systems. This will be accomplished by using two powerful molecular genetic approaches for creation of complex natural products along with sophisticated "smart assays" for molecular-based screening at Novartis Pharmaceuticals. Five research groups will work together to access unique marine microbial genomes, generate combinatorial biology and combinatorial biosynthesis libraries, culture and extract novel metabolites, screen extracts for anti-cancer biological activity and characterize new chemical entities. Project #1 is headed by Dr. Amy Wright at Harbor Branch Oceanographic Institution (HBOI) who will collect and characterize novel marine actinomycetes. Dr. Peter McCarthy at HBOI will direct the core facility and manage microbial genomic DNA preparation, fermentation and extraction for the combinatorial biology clones. Project #2 is headed by Dr. David H. Sherman at the University of Minnesota, the overall P.I., who will direct the combinatorial biology as well as combinatorial biosynthesis efforts for the entire program. The administrative core will also be managed by Dr. Sherman. Team #3 is headed by Dr. Kenneth Blair of the Oncology Department at Novartis Pharmaceuticals. His group will be responsible for high throughput screening using "smart assays" developed for anti-cancer drug discovery. Project #4, headed by Dr. William Gerwick at Oregon State University, will focus on isolation and characterization of novel marine cyanobacteria for generation of combinatorial biology libraries. His group will also participate in combinatorial biosynthesis work on the curacin A polyketide synthase. Project #5 of this highly collaborative and interactive effort, headed by Dr. Phillip Crews of U.C. Santa Cruz, will focus on isolation and identification of novel marine microbes, including sponge- derived actinomycetes, myxobacteria and fungi. His laboratory will provide genomic source material for combinatorial biology as well as for combinatorial biosynthesis on the latrunculin A polyketide synthase. Both the Wright, Gerwick and Crews laboratories will each provide natural products purification and structure elucidation support. In summary, unique compound structural diversity will be generated by this multi- disciplinary collaboration.